1. Field of the Invention
This invention relates to a novel series of semibiosynthetic tallysomycin derivatives which have advantageous antimicrobial and antitumor properties.
2. Description of the Prior Art
Although a number of glycopeptide antibiotics have been discovered, some of which are also effective in inhibiting the growth of tumors in mammals, there remains a need for additional antimicrobial and antitumor agents. Especially needed are antitumor agents which exhibit increased activity and/or broader spectrum relative to presently available agents or which show fewer undesirable side effects. A brief summary of the more important glycopeptide antibiotics is provided below.
The bleomycins are water-soluble basic glycopeptides produced by fermentation of Streptomyces verticillus. They were first reported by Umezawa et al. in J. Antibiotics 19A:200 (1966); see also U.S. Pat. No. 3,681,491. The bleomycin complex has been separated into several components including bleomycin A.sub.1, A.sub.2, A.sub.5 and B.sub.2. Bleomycin complex is presently being marketed for treatment of various neoplasms in man including squamous cell carcinoma, lymphosarcoma, reticulum cell sarcoma, testicular carcinoma and Hodgkin's disease. A revised structure for the bleomycins has recently been published by H. Umezawa et al. in J. Antibiotics 31:801-804 (1978).
The phleomycin group of antibiotics obtained from fermentation of another strain of Streptomyces verticillus has been reported by Maeda et al. in J. Antibiotics: Vol. A9, pg. 82-85 (1956); Vol. A12, p. 111 (1959); Vol. A12, pg. 285-289 (1959) and Vol. A17, pg. 194-199 (1964). As with bleomycin complex, phleomycin has been separated into a number of components which can exist in both a copper-free and a copper-chelated form.
Zorbamycin and its related antibiotics zorbonomycin B and zorbonomycin C are reported in J. Antibiotics 24(8): 543-557 (1971) and in U.K. Pat. No. 1,277,150. These antibiotics isolated from fermentations of Streptomyces bikiniensis var. zorbonensis are closely related to the bleomycin and phleomycin families.
Another family of phleomycin-bleomycin group antibiotics has been isolated from the culture broth of a variant of Streptomyces humidus and given the name YA-56. A description of the YA-56 complex and active components YA-56X and YA-56Y appears in J. Antibiotics 24(10): 727-731 (1971) and in J. Antibiotics 26: 77-83 (1973).
The antibiotic complex XK 49 and its main component victomycin (also called XK 49-1-B-2) are reported in J. Antibiotics 28: 358-371 (1975). Victomycin is isolated from a sporangia-forming actinomycete, Streptosporangium violaceochromogenes MK 49, and appears to be similar to the bleomycins and zorbonomycin B.
The glycopeptide antibiotic complex Bu-2231 and its components Bu-2231 A and B [hereinafter referred to as tallysomycin and tallysomycin A and B, respectively) are disclosed in U.S. Pat. No. 4,051,237; see also J. Antibiotics: Vol. 30, pg. 779-805 (1977) and Vol. 31, pg. 667-674 (1978)]. The tallysomycins are isolated from the fermentation broth of certain Streptoalloteichus hindustanus strains and exhibit potent antimicrobial and antitumor activities.
Preparation of various semibiosynthetic derivatives of phleomycin and bleomycin by the technique of precursor-fed fermentation has been disclosed in U.S. Pat. Nos. 3,984,390 and 3,846,400. In this procedure strains of microorganisms capable of producing the phleomycin or bleomycin antibiotics are cultured in a fermentation medium in the presence of an amine precursor to produce new phleomycin or bleomycin derivatives having a side chain structure corresponding to the added amine.
U.K. Published Application 2,001,962 A discloses preparation of 3-[(S)-1'-phenylethylamino]propylaminobleomycin (pepleomycin) as an especially preferred semibiosynthetic bleomycin derivative because of its combination of potent antitumor activity and low pulmonary toxicity.